Macrophage-stimulating protein (MSP) mediates its biological activities via binding and activation of the receptor tyrosine kinase Ron, a member of the Met-proto-oncogene family (Leonard & Danilkovitch, 2000). Interaction of MSP with its receptor leads to receptor phosphorylation and kinase activation. The MSP/Ron pathway has been implicated in tumorigenesis of various cancers (see, e.g., Wagh et al., 2008). MSP is a plasma protein which is constitutively synthesized in hepatic parenchymal cells primarily, but it is also expressed in lung, adrenal gland and placenta in low levels. MSP circulates in blood as an inactive single-chain precursor (pro-MSP), which requires proteolytic cleavage at the Ser-Lys-Leu-Arg483↓Val484 (SEQ ID NO:1) bond to attain functional activity (Skeel et al., 1991) (Yoshimura et al., 1993). Active MSP is a heterodimer of α- and the β-subunits held together by a disulfide bond. MSP was known to be activated at the extravascular site by several trypsin-like serine proteases (Bhatt et al., 2007; Kawaguchi et al., 2009; Wang et al., 1994b; Wang et al., 1996; Wang et al., 1994c).
Hepsin is a member of the type II transmembrane serine protease family (Netzel-Arnett et al., 2003; Wu & Parry, 2007) and was identified as one of the most highly upregulated genes in prostate cancer (Dhanasekaran et al., 2001; Luo et al., 2001; Magee et al., 2001; Stamey et al., 2001; Stephan et al., 2004; Welsh et al., 2001) Immunohistochemical staining revealed strong expression in late stage tumors and metastatic bone lesions (Morrissey et al., 2008; Xuan et al., 2006) suggesting a role of hepsin in tumor progression. Moreover, based on gene expression analysis hepsin has also been implicated in ovarian cancer (Tanimoto et al., 1997), renal cell carcinoma (Betsunoh et al., 2007; Zacharski et al., 1998) and endometrial cancer (Matsuo et al., 2008). Beliveau et al stated that hepsin does not cleave pro-MSP (Beliveau et al., (2009) FEBS J. 276:2213-26).
There is a clear need for a comprehensive understanding of hepsin's physiological substrates. The invention fulfills this need and provides other benefits.
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